TY - JOUR
T1 - Common non-synonymous SNPs associated with breast cancer susceptibility
T2 - findings from the Breast Cancer Association Consortium
AU - Milne, Roger L
AU - Burwinkel, Barbara
AU - Michailidou, Kyriaki
AU - Arias-Perez, Jose-Ignacio
AU - Zamora, M Pilar
AU - Menéndez-Rodríguez, Primitiva
AU - Hardisson, David
AU - Mendiola, Marta
AU - González-Neira, Anna
AU - Pita, Guillermo
AU - Alonso, M Rosario
AU - Dennis, Joe
AU - Wang, Qin
AU - Bolla, Manjeet K
AU - Swerdlow, Anthony
AU - Ashworth, Alan
AU - Orr, Nick
AU - Schoemaker, Minouk
AU - Ko, Yon-Dschun
AU - Brauch, Hiltrud
AU - Hamann, Ute
AU - Andrulis, Irene L
AU - Knight, Julia A
AU - Glendon, Gord
AU - Tchatchou, Sandrine
AU - Matsuo, Keitaro
AU - Ito, Hidemi
AU - Iwata, Hiroji
AU - Tajima, Kazuo
AU - Li, Jingmei
AU - Brand, Judith S
AU - Brenner, Hermann
AU - Dieffenbach, Aida Karina
AU - Arndt, Volker
AU - Stegmaier, Christa
AU - Lambrechts, Diether
AU - Peuteman, Gilian
AU - Christiaens, Marie-Rose
AU - Smeets, Ann
AU - Jakubowska, Anna
AU - Lubinski, Jan
AU - Jaworska-Bieniek, Katarzyna
AU - Durda, Katazyna
AU - Hartman, Mikael
AU - Hui, Miao
AU - Yen Lim, Wei
AU - Cross, Simon S
AU - Reed, Malcolm W R
AU - Hwang Teo, Soo
AU - Stewart-Brown, Sarah
AU - GENICA Network
N1 - © The Author 2014. Published by Oxford University Press.
PY - 2014/11/15
Y1 - 2014/11/15
N2 - Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
AB - Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
KW - A Kinase Anchor Proteins
KW - Adult
KW - Alleles
KW - Ataxin-7
KW - Breast Neoplasms
KW - Case-Control Studies
KW - Cytoskeletal Proteins
KW - Female
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Humans
KW - Middle Aged
KW - NIMA-Related Kinases
KW - Nerve Tissue Proteins
KW - Polymorphism, Single Nucleotide
KW - Protein-Serine-Threonine Kinases
KW - Journal Article
KW - Research Support, N.I.H., Extramural
KW - Research Support, Non-U.S. Gov't
KW - Research Support, U.S. Gov't, Non-P.H.S.
KW - Research Support, U.S. Gov't, P.H.S.
U2 - 10.1093/hmg/ddu311
DO - 10.1093/hmg/ddu311
M3 - Article (Academic Journal)
C2 - 24943594
SN - 0964-6906
VL - 23
SP - 6096
EP - 6111
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 22
ER -